Modelling depression in animals and the potential antidepressant effect of histaminergic modulation

Depression is at the top position for "years lived with disability" (Smith, 2014). Its aetiology is unknown, but the pathogenesis implicates changes in glutamatergic neuronal plasticity. Glutamatergic plasticity likely mediates the effects of antidepressants acting through monoamines. Histamine is a monoaminergic neuromodulator able to regulate glutamatergic plasticity and synaptic transmission.

The Flinders sensitive line (FSL) rat has face and predictive validity as model of depression when using traditional behavioural tests. However, these tests are usually missing complex explorative strategies that the animal performs in novel situations and that may be a relevant feature for a model of depression. We aimed to profile the FSL rat in terms of explorative strategies and coping styles displayed in a novel environment. The multivariate concentric square field™ (MCSF) consists of zones with different degrees of aversion. In the MCSF test, FSL rats showed lower exploratory drive, less recurrence to the shelter, and more risk assessment compared to Sprague Dawley rats, but no difference in risk-taking behaviours. In the novel cage test (consisting in a new bare environment) and in the home cage change test (to measure social behaviours), the FSL rat displayed a reactive coping style, described by immobility and lower aggression compared to Sprague Dawley rats. This profile shows similarities with temperaments and coping styles related to depression.

Depression is linked to alteration of glutamatergic plasticity and similar alterations have been found in the hippocampus of FSL rats. Histamine H3 receptor (H3R) antagonists have displayed antidepressant properties in preclinical studies. We assessed the antidepressant properties of the H3R antagonist, clobenpropit, and its effect on hippocampal glutamatergic transmission in FSL rats. In the forced swim test, both systemic and hippocampal injections of clobenpropit reduced the immobility time. Clobenpropit improved memory in the novel object recognition and passive avoidance tests, with no effect on anxiety-related tests. Clobenpropit applied on hippocampal slices enhanced long-term synaptic potentiation (LTP), and, accordingly, in vivo administration increased the hippocampal levels of the NMDA receptor subunit GluN2A. Clobenpropit's effects both in the forced swim test and on LTP were prevented by blocking the hippocampal H1 and H2 receptors. In summary, clobenpropit exhibits antidepressant properties and regulates hippocampal glutamatergic plasticity, likely by an increase of histamine release and subsequent activation of the H1 and H2 receptors.

Histamine receptors trigger intracellular signalling involved in the regulation of glutamatergic synaptic receptors, a mechanism that can affect synaptic strength. We assessed the histaminergic modulation of glutamatergic synaptic strength by recording miniature excitatory postsynaptic currents (mEPSCs) from CA1 pyramidal neurons in hippocampal slices from Sprague Dawley rats. The H1R, but not the H2R, agonist reduced mEPSC frequency, with no change of amplitude, suggesting a reduction of vesicle release probability. However, the paired-pulse facilitation (a measure of presynaptic release probability) was not altered by either the H1R or the H2R agonist, possibly due to a differential modulation of evoked versus spontaneous vesicle release. However, a postsynaptic origin of mEPSC frequency reduction cannot be excluded.

List of scientific papers

I. Magara S., Holst S., Lundberg S., Roman E., Lindskog M. Altered explorative strategies and reactive coping style in the FSL rat model of depression. Front Behav Neurosci. 21 April 2015.
https://doi.org/10.3389/fnbeh.2015.00089

II. Femenia T., Magara S., DuPont C.M., Lindskog M. Hippocampal-dependent antidepressant action of the H3 receptor antagonist clobenpropit in a rat model of depression. Int J Neuropsychopharmacol. 2015.
https://doi.org/10.1093/ijnp/pyv032

III. Magara S., Lindskog M. Histamine H1 and H2 receptor-mediated modulation of glutamatergic synaptic strength in the hippocampus. [Manuscript]